Clinical benefits of switching to insulin degludec irrespective of previous basal insulin therapy in people with Type 1 or Type 2 diabetes: evidence from a European, multicentre, retrospective, non-interventional study (EU-TREAT).

AIMS: To investigate whether the benefits of switching to insulin degludec observed in the European retrospective chart review study EU-TREAT were dependent on the previous basal insulin used. METHODS: People with Type 1 or Type 2 diabetes were switched to insulin degludec from other basal insulins ≥6 months before data collection. Participants were stratified into three groups based on their previous basal insulin: insulin glargine 100 units/ml (Type 1: n=888; Type 2: n=259); insulin detemir (Type 1: n=726; Type 2: n=415); and neutral protamine Hagedorn (Type 1: n=53; Type 2: n=95). Their glycaemic control and hypoglycaemia incidence at 6 and 12 months post-switch vs pre-switch was then evaluated. RESULTS: Significant HbA1c reductions were achieved in all previous basal insulin groups for participants with Type 1 diabetes [insulin glargine 100 units/ml: -2.08 mmol/mol (-0.19%); insulin detemir: -2.40 mmol/mol (-0.22%)] and those with Type 2 diabetes [insulin glargine 100 units/ml: -5.90 mmol/mol (-0.54%); insulin detemir: -6.01 mmol/mol (-0.55%); neutral protamine Hagedorn: -2.73 mmol/mol (-0.25%)] at 6 months, except for the relatively small neutral protamine Hagedorn group in those with Type 1 diabetes [-1.75 mmol/mol (-0.16%)], where statistical significance was not reached. At 6 months in the Type 1 diabetes group, switching to insulin degludec from insulin glargine 100 units/ml resulted in significantly lower hypoglycaemia rates across all hypoglycaemia categories; for the insulin detemir group, this significance was also observed for severe and nocturnal non-severe hypoglycaemia, while the low number of people in the neutral protamine Hagedorn group resulted in nonsignificant reductions in hypoglycaemia rates. At 6 months in the people with Type 2 diabetes, switching to insulin degludec resulted in significantly lower rates of hypoglycaemia across all categories for all groups. Similar outcomes were observed at 12 months. CONCLUSIONS: Switching to insulin degludec from other basal insulins can improve glycaemic control and/or reduce hypoglycaemia risk in people with diabetes (although there was a nonsignificant reduction in HbA1c and hypoglycaemia rates for the neutral protamine Hagedorn group in Type 1 diabetes) under routine care.

Plasma omentin-1 levels are related to exercise performance in obese women and increase upon aerobic endurance training.

INTRODUCTION: Omentin-1 is an adipokine that is primarily released from visceral adipose tissue stromal cells. The effects of exercise on omentin-1 regulation are not clear so far. Therefore, the effect of endurance training on circulating omentin-1 levels and its relation to exercise performance was assessed in obese women. METHODS: 13 obese women (age: 44.8±3.3 years; BMI: 37.8±1.3 kg·m(-2)) participated in a 6-week endurance training program. Omentin-1, metabolic traits (glucose, insulin, HOMA-IR, lipids profile), and exercise performance (cardiopulmonary exercise test (V̇O2,peak, Wpeak), 6 min walking test, 6MWT) were assessed before and after the training. RESULTS: After the training program circulating omentin-1 were 10.4% higher than before the program (690±50 ng·ml(-1) vs. 618±42; p=0.04), while body weight remained unchanged (p=0.9). Before training, omentin-1 levels were significantly correlated with Wpeak (given in absolute and relative values) as well as with 6MWT (all r≥0.603; all p≤0.029) and the correlations with absolute as well as relativeV̇O2,peak approached significance (both r≥0.534; both p≤0.060). After training, respective correlations were generally weaker and did not reach significance any longer (all r≤0.465; all p≥0.109). Neither before nor after the training program were significant correlations found between omentin-1 levels and the other measured metabolic blood markers (all p≥0.157). DISCUSSION: Data show a rather strong relationship between exercise performance and circulating omentin-1 levels as well as an increase of the adipokine in response to 6-week of endurance training in obese women. Our findings may hint to a skeletal muscle-adipose tissue crosstalk in regard of omentin-1 regulation.

Cardio-respiratory fitness is independently associated with cardio-metabolic risk markers in severely obese women.

INTRODUCTION: Many studies have shown an inverse relationship between cardio-respiratory fitness and cardio-metabolic risk markers in normal-weight to moderately obese subjects. However, whether such a relationship exists in severely obese subjects is not known. MATERIALS AND METHODS: Cardio-respiratory fitness was measured by bicycle spiroergometry in 308 severely obese women (all BMI>35 kg/m(2)). The following cardio-metabolic risk markers were assessed: Glycolized hemoglobin levels (HbA1c), fasting glucose, insulin, calculated HOMA index, triglycerides (TG), total, low-, high-density cholesterol (Chol, LDL; HDL), Chol/HDL-Ratio, and uric acid. Computed multiple stepwise linear regression models generally included age, weight and height as independent variables. RESULTS: Multiple stepwise linear regression models indicated that peak but not aerobic threshold related cardio-respiratory fitness indices were independently of age, weight and height associated with several cardio-metabolic risk markers. Specifically, maximally achieved load (Watt-peak) explained 1.4% of the variance in glucose levels (beta= -0.13; p=0.04) and 2.8% of the variance in HbA1c levels (beta= -0.18; p=0.01), while maximally achieved O2-uptake explained 3.9% of the variance in TG levels (beta= -0.20, p=0.001). CONCLUSION: Our data for the first time indicate that cardio-respiratory fitness is independently associated with cardio-metabolic risk markers in severely obese women.

Correction factors for the calculation of metabolic equivalents (MET) in overweight to extremely obese subjects.

BACKGROUND/OBJECTIVES: The metabolic equivalent (MET) is a construct that is commonly used to quantify physical activity as well as exercise performance. 'One MET' is equal to a resting oxygen uptake of 3.5 ml O2 kg(-1) min(-)(1). However, this assumption is unlikely valid in obese subjects. The aim of our study was to quantify the difference between calculated and measured METs in overweight to severely obese subjects and to provide body mass index (BMI)-specific MET correction factors. SUBJECTS/METHODS: Resting oxygen uptake (VO2-REE) was measured in 1331 patients with a BMI >25 kg m(-2) (72.0% women; age: 42.5 ± 13.0 years; BMI: 42.5 ± 7.0 kg m(-)(2)) by indirect calorimetry and MET-REE, that is, VO2-REE related to body weight was calculated. Six hundred and fifty-two subjects (70.9% women) additionally underwent a bicycle cardiopulmonary exercise test for measurement of maximal MET (MET peak). RESULTS: Mean MET-REE was 2.47 ± 0.33 ml O2 kg(-1) min(-1) in women and 2.62 ± 0.34 ml O2 kg(-1) min(-1) in men, that is, markedly lower than the expected 3.5 ml O2 kg(-1) min(-1). MET-REE decreased with increasing BMI (P<0.001 for both sexes). On this dataset, gender-specific MET correction factors were developed for distinct BMI groups. During the exercise test, women performed 4.4 ± 1.3 MET peak and men 4.7 ± 1.3. After applying our correction factors, MET peak increased to 6.2 ± 1.7 and 6.1 ± 1.6, respectively. CONCLUSIONS: Data indicate that the commonly used 1-MET value of 3.5 ml O2 kg(-)(1) min(-)(1) largely overestimates values in overweight to severely obese subjects. Our correction factors can help to reduce this systematic error and thus appear to be valuable for clinical practice as well as research studies.

Altered brain activity in severely obese women may recover after Roux-en Y gastric bypass surgery.

OBJECTIVE: Neuroimaging studies have demonstrated alterations in brain activity in obese (OB) subjects that might be causally linked to their disorder. Roux-en Y gastric bypass (RYGB) surgery induces a marked and sustained weight loss and may affect brain activity. The aim of this study was to compare brain activity pattern between severely OB women (n=11), normal-weight women (NW, n=11) and previously severely OB women who had undergone RYGB surgery (RYGB, n=9) on average 3.4±0.8 years (all >1 year) before the experiment. DESIGN: Brain activity was assessed by functional magnetic resonance imaging during a one-back task containing food- and non-food-related pictures and during resting state. Hunger and satiety were repeatedly rated on a visual analog scale during the experiment. RESULTS: As compared with NW and also with RYGB women, OB women showed (1) a higher cerebellar and a lower fusiform gyrus activity during the visual stimulation independently of the picture category, (2) a higher hypothalamic activation during the presentation of low- vs high-caloric food pictures, (3) a higher hippocampal and cerebellar activity during the working memory task and (4) a stronger functional connectivity in frontal regions of the default mode network during resting state. There were no differences in brain activity between the NW and RYGB women, both during picture presentation and during resting state. RYGB women generally rated lower on hunger and higher on satiety, whereas there were no differences in these ratings between the OB and NW women. CONCLUSION: Data provide evidence for an altered brain activity pattern in severely OB women and suggest that RYGB surgery and/or the surgically induced weight loss reverses the obesity-associated alterations.

The hedonic drive to consume palatable foods appears to be lower in gastric band carriers than in severely obese patients who have not undergone a bariatric surgery.

BACKGROUND: We have recently shown that severely obese patients display a markedly enhanced drive to consume palatable food, and that this hedonic hunger is reduced after gastric bypass surgery. Adjustable gastric banding is another frequently performed bariatric operation with unknown effects on hedonic hunger motivation. Here, we compared the level of hedonic hunger in patients who have undergone a gastric banding with that in severely obese patients who have not undergone a bariatric operation and nonobese controls. METHODS: In a cross-sectional case-control study, 116 gastric banding patients, 138 severely obese patients, and 133 nonobese controls were examined with the Power of Food Scale (PFS), a questionnaire that reliably measures an individual's motivation to consume highly palatable food. RESULTS: While the severely obese patients displayed markedly higher aggregated PFS scores and scores on the subdomain "generally available" and "physically present" food than the nonobese controls (all P < 0.001), the gastric banding patients showed significantly lower scores on all of these variables than the obese patients (all P < 0.001). However, the generally available food score was still higher in gastric banding patients than in the nonobese controls (P = 0.001). CONCLUSIONS: Data suggest that adjustable gastric banding may reduce the excessive appetite for palatable foods in severely obese patients. This suggestion needs to be confirmed in longitudinal studies.

Whole body vibration added to endurance training in obese women - a pilot study.

Whole body vibration (WBV) training is an increasingly popular training method that is strongly promoted for weight loss, but scientific data on its effectiveness, particularly in obese subjects, are sparse. 14 obese women (BMI: 37.4 ± 1.3 kg/m2) randomized to 2 different groups (each n=7) participated in a 6-week endurance training program that was either combined or not combined with additional WBV training. Anthropometric measures, phase angle and body composition (assessed by bioelectrical impedance analysis; BIA), and resting energy expenditure (REE) were obtained before and after the training program. Body weight did not change during the training period (P=0.87), but waist circumference decreased in both groups (P=0.007; WBV: -3.4 ± 1.4 cm; no-WBV: -1.7 ± 0.7 cm) independent of WBV training (P=0.29 for group×time interaction). BIA revealed an enhancing effect of WBV training in comparison to no-WBV training on the phase angle (+0.20 ± 0.12° vs. -0.19 ± 0.12°; P=0.04) and calculated body cell mass (+0.8 ± 0.2 vs. -0.3 ± 0.4 kg; P=0.02), while calculated percentage fat mass decreased in both conditions (P=0.05) to similar extent (P=0.59; WBV: -0.8 ± 0.2%; no-WBV: -0.4 ± 0.5%). REE increased across the training (P=0.01; WBV: +77 ± 33 kcal/24 h; no-WBV: +68 ± 34 kcal/24 h), with this increase again not depending on WBV condition (P=0.85). Results of our pilot study in obese women provide preliminary evidence for a beneficial effect of WBV, when added to endurance training, on the bioelectrical phase angle, an increasingly recognized marker of individual's health status.

Intranasal administration of insulin to the brain impacts cognitive function and peripheral metabolism.

In recent years, the central nervous system (CNS) has emerged as a principal site of insulin action. This notion is supported by studies in animals relying on intracerebroventricular insulin infusion and by experiments in humans that make use of the intranasal pathway of insulin administration to the brain. Employing neurobehavioural and metabolic measurements as well as functional imaging techniques, these studies have provided insight into a broad range of central and peripheral effects of brain insulin. The present review focuses on CNS effects of insulin administered via the intranasal route on cognition, in particular memory function, and whole-body energy homeostasis including glucose metabolism. Furthermore, evidence is reviewed that suggests a pathophysiological role of impaired brain insulin signaling in obesity and type 2 diabetes, which are hallmarked by peripheral and possibly central nervous insulin resistance, as well as in conditions such as Alzheimer's disease where CNS insulin resistance might contribute to cognitive dysfunction.

[Disturbed sleep as risk factor for metabolic syndrome]. / Schlechter Schlaf als Risikofaktor für das metabolische Syndrom.

Sleep disorders, sleep fragmentation, and chronically reduced sleep duration are increasingly common in western societies. In parallel, incidence of the metabolic syndrome and its key components, i.e. type 2 diabetes and obesity, is rapidly increasing. A huge number of epidemiological studies has shown a robust association between disturbed sleep quality, reduced sleep duration and the development of components of the metabolic syndrome. Moreover, there is growing evidence from experimental studies proving a causal link between sleep loss and disturbed human energy homeostasis. Short term sleep loss has been shown to reduce insulin sensitivity and glucose tolerance, increase feelings of hunger by modulating orexigenic/anorexigenic hormonal signaling, and disturb physical activity behavior. This review attempts to present an overview of the presently available literature on the link between sleep loss and disturbed human energy homeostasis, as well as on potential pathophysiological mechanisms.

[Procaine infusion for pain treatment of acute pancreatitis: a randomized, placebo-controlled double-blind trial]. / Procaininfusion zur Schmerzbehandlung bei akuter Pankreatitis: Eine randomisierte, placebokontrollierte Doppelblind-Studie.

BACKGROUND AND OBJECTIVE: Acute pancreatitis is commonly associated with severe abdominal pain, making early pain relief a primary goal of the treatment. This study was undertaken to assess the efficacy of a continuous intravenous (i.v.) infusion of procaine compared with that of a placebo infusion in providing pain relief in patients with acute pancreatitis. PATIENTS AND METHODS: 42 patients with acute pancreatitis were prospectively randomized to receive, in a double-blind setting, a continuous i.v. infusion of a 1% solution of procaine (procaine group) or placebo (placebo group, receiving a 0.9% saline solution) on the first three days of treatment in a hospital setting. The maximal infusion rate of the procaine solution was 8 ml/h, i.e. 1.92 g/24 h. The rate and total amount of infused fluid was similar in the placebo group. Additionally buprenorphine (Temgesic, sublingual [s.l.]) were given on demand for additional pain relief. RESULTS: The gender ratio and the severity of the pancreatitis (APACHE II score, Ranson score) were comparable between the two groups, while the patients of the control group were eight years older (50.1 2.3 vs. 58.4 3.1; p = 0.039). The i.v. infusion of procaine did not reduce the demand for buprenorphine in the procaine group and was similar to that in the placebo group (p=0.88). Furthermore, explorative data analysis revealed that patients of the procaine group had higher bodily discomfort and nausea scores and also tended to feel more pain than the patients of the placebo group. DISCUSSION: These data do not indicate a clinically meaningful analgesic effect of i.v. infusion of procaine (maximal amount. 1.92 g/24h) in patients with acute pancreatitis, but suggested that this infusion actually increased the feeling of bodily discomfort and nausea. We thus conclude that a constant i.v. infusion of procaine should no longer be recommended for pain relief in patients with acute pancreatitis anymore.

The effect of 6-weeks of aerobic exercise training on serum fetuin-A levels in non-diabetic obese women.

Emerging evidence suggests that fetuin-A, a liver-derived glycoprotein, represents an important factor in the pathophysiology of the metabolic syndrome, type 2 diabetes and cardiovascular disease. So far circulating fetuin-A was found to be increased in fatty liver disease, however, the precise mechanisms regulating fetuin-A expression and secretion are largely unknown. Here we assessed serum fetuin-A levels in 14 non-diabetic, obese women (BMI 36.5 ± 1.5 kg/m (2)) before and after a 6-week aerobic exercise program. Despite decreasing waist circumference (from 114.9 ± 3.5 to 112.3 ± 3.2 cm; P = 0.006) and body fat content (from 44.1 ± 1.5% to 43.4 ± 1.5%; P = 0.022) regular exercise 3-times per week over a 6-week period did not affect serum fetuin-A levels (before vs. after: 0.440 ± 0.018 vs. 0.440 ± 0.014 µg/ml; P = 0.767). Thus, our data provide evidence against a major role of exercise in the regulation of serum fetuin-A levels in non-diabetic obese women.

Central nervous insulin resistance: a promising target in the treatment of metabolic and cognitive disorders?

Research on functions and signalling pathways of insulin has traditionally focused on peripheral tissues such as muscle, fat and liver, while the brain was commonly believed to be insensitive to the effects of this hormone secreted by pancreatic beta cells. However, since the discovery some 30 years ago that insulin receptors are ubiquitously found in the central nervous system, an ever-growing research effort has conclusively shown that circulating insulin accesses the brain, which itself does not synthesise insulin, and exerts pivotal functions in central nervous networks. As an adiposity signal reflecting the amount of body fat, insulin provides direct negative feedback to hypothalamic nuclei that control whole-body energy and glucose homeostasis. Moreover, insulin affects distinct cognitive processes, e.g. by triggering the formation of psychological memory contents. Accordingly, metabolic and cognitive disorders such as obesity, type 2 diabetes mellitus and Alzheimer's disease are associated with resistance of central nervous structures to the effects of insulin, which may derive from genetic polymorphisms as well as from long-term exposure to excess amounts of circulating insulin due to peripheral insulin resistance. Thus, overcoming central nervous insulin resistance, e.g. by pharmacological interventions, appears to be an attractive strategy in the treatment and prevention of these disorders. Enhancement of central nervous insulin signalling by administration of intranasal insulin, insulin analogues and insulin sensitisers in basic research approaches has yielded encouraging results that bode well for the successful translation of these effects into future clinical practice.

Blocking AMPA receptor signalling by caroverine infusion does not affect counter-regulation of hypoglycaemia in healthy men.

AIMS/HYPOTHESIS: Glutamatergic pathways are assumed to play a critical role in the hormonal stress response to hypoglycaemia. In rats, glutamate signalling at the amino-3-hydroxy-5-methyl-4-isoxazol propionate (AMPA) receptor contributes to hormone release induced by behavioural stressors. We hypothesised that blocking the AMPA receptor by caroverine in healthy men would impair their perception of neuroglycopenia and thereby diminish hormonal counter-regulation as well as symptoms of hypoglycaemia, as a model of stress. METHODS: In a balanced double-blind study, two hypoglycaemic clamp sessions (mean blood glucose 2.4 mmol/l for 50 min) were performed in ten healthy men during intravenous administration of 80 mg caroverine or placebo. We assessed concentrations of counter-regulatory hormones as well as subjective symptoms related to hypoglycaemia. RESULTS: AMPA receptor antagonisation by caroverine did not influence the perception of neuroglycopenic and autonomic hypoglycaemia-associated symptoms (p > 0.39 for all). Notwithstanding, caroverine did increase basal and counter-regulatory glucagon secretion (p < 0.002) and slightly enhanced counter-regulatory growth hormone concentrations (p = 0.07). Counter-regulatory release of ACTH, cortisol, adrenaline (epinephrine) and noradrenaline (norepinephrine) did not differ between conditions (p > 0.11 for all). CONCLUSIONS/INTERPRETATION: Antagonising AMPA receptor signalling by caroverine infusion failed to diminish and even slightly amplified counter-regulatory hormone release during hypoglycaemia in healthy men. The discrepancy with previous findings in rats may be due to different dosages or administration routes and calls for further investigations on the role of AMPA receptor signalling in hypoglycaemia counter-regulation in humans.

Short-term nocturnal hypoglycaemia increases morning food intake in healthy humans.

AIMS: Hypoglycaemia during wakefulness increases hunger and food intake. Patients with Type 1 diabetes mellitus are at high risk of recurrent hypoglycaemia and weight gain. Given the background of frequent hypoglycaemic episodes during night-time sleep in diabetic patients, we investigated morning food intake after nocturnal hypoglycaemia. METHODS: We tested 16 healthy normal-weight subjects (eight women) on three nights. A linear fall in plasma glucose to a nadir of 2.2 mmol/l within 60 min was induced by insulin infusion immediately after sleep onset ('early hypo') or after about 3.5 h of sleep ('late hypo'). On a control night, no hypoglycaemia was induced. Spontaneous food intake at a breakfast buffet was registered on the subsequent morning. RESULTS: Compared with the control condition (700 +/- 93 kcal), subjects ate more after 'late hypo' (867 +/- 108 kcal; P = 0.041), but not after 'early hypo' (852 +/- 111 kcal; P = 0.130). Analyses of macronutrient fractions revealed that in comparison with the control condition, subjects ate significantly more carbohydrates after both 'late hypo' (277 +/- 25 kcal vs. 206 +/- 23 kcal, P < 0.001) and 'early hypo' (245 +/- 23 kcal, P = 0.048), with this effect being more pronounced after late than early nocturnal hypoglycaemia (P = 0.026). CONCLUSIONS: In healthy subjects, nocturnal hypoglycaemia during sleep stimulates spontaneous food intake the following morning, with carbohydrate intake being especially affected. Effects were more pronounced after 'late hypo', suggesting the influence of temporal dynamics. Although healthy non-diabetic subjects were studied, similar mechanisms may contribute to the frequently observed body weight gain in insulin-treated diabetic patients.

Obese men respond to cognitive but not to catabolic brain insulin signaling.

CONTEXT AND OBJECTIVE: Insulin acts in the brain to reduce food intake and body weight and is considered a major adiposity signal in energy homeostasis. In normal-weight men, intranasal insulin administration reduces body fat and improves declarative memory. The present experiments aimed to generalize these findings to obese patients, with a view to evaluate the therapeutic potential of the compound. DESIGN, SUBJECTS AND MEASUREMENTS: Insulin and placebo, respectively, were intranasally administered four times a day (amounting to 160 IU day(-1)) over 8 weeks to two groups of 15 obese men each. RESULTS: Contrasting with the catabolic effects in normal-weight men, insulin treatment did not induce any significant reduction of body weight (P>0.50) and body fat (P>0.44) in the obese subjects. However, in accordance with the effects in normal-weight men, declarative memory and mood were improved (P<0.05) and hypothalamic-pituitary-adrenal axis activity as assessed by circulating ACTH (P<0.01) and cortisol levels (P<0.04) was reduced. CONCLUSIONS: Our results indicate that in obese men, intranasal insulin is functionally active in the central nervous system but fails to affect the neuronal networks critically involved in body weight regulation. We conclude that obesity in men is associated with central nervous resistance to the adiposity signal insulin. This defect likely contributes to the persistence of obesity in spite of elevated levels of circulating insulin in obese patients.

Plasma glucagon decreases during night-time sleep in Type 1 diabetic patients and healthy control subjects.

AIMS: In Type 1 diabetes mellitus (T1DM), the glucagon response to hypoglycaemia is known to disappear within a few months after the onset of the disease, whereas the response to other stimuli remains intact. The dynamics of spontaneous glucagon release have rarely been assessed. We monitored spontaneous glucagon release in T1DM patients and healthy subjects during a 7-h period of night-time sleep. METHODS: Measurements were made in 14 T1DM patients and 14 control subjects matched for age, gender and body mass index after one night's adaptation in our laboratory. Circulating glucose, insulin and glucagon concentrations were measured at 30-min intervals. In diabetic patients, hypoglycaemia (< 3.9 mmol/l) was avoided by infusion of glucose whenever necessary. RESULTS: During the entire night, plasma glucose and serum insulin levels were higher in T1DM patients than in healthy subjects (P < 0.03 and P < 0.001, respectively). Plasma glucagon concentrations decreased throughout the night in both groups (P < 0.001). Glucagon levels were similar in T1DM patients and healthy subjects (P > 0.87). The duration of diabetes (less and more than 5 years) did not affect glucagon secretion (P > 0.87). CONCLUSIONS: Plasma glucagon levels decrease significantly during night-time sleep in healthy control subjects. This nocturnal decrease is preserved in T1DM patients regardless of the duration of diabetes. These observations point to distinct nocturnal regulation of spontaneous glucagon release that does not depend on circulating glucose and insulin levels and is unaltered in T1DM patients.

Mood and cognitive functions during acute euglycaemia and mild hyperglycaemia in type 2 diabetic patients.

INTRODUCTION: Hyperglycaemia at levels above 15 mmol/l has been shown to impair cognitive functions in type 2 diabetic patients, while effects of mild hyperglycaemia and acute euglycaemia on mood and cognition have rarely been compared. We examined mood and cognitive functions in patients with T2DM during acute euglycaemia in comparison with moderate hyperglycaemia. METHODS: One euglycaemic (5 mmol/l) and one hyperglycaemic clamp (10.5 mmol/l) of 90 min each were performed in 15 T2DM patients in a balanced, single-blind, within-subject comparison. Mood, cognitive functions (assessed via short-term memory and attention tests) and symptoms related to glycaemic changes were assessed during a baseline period and during both glycaemic plateaus. In addition, patients estimated their blood glucose level and counterregulatory hormones were measured. RESULTS: None of the assessed aspects of cognitive functions differed between conditions (all p > or = 0.2). Patients rated higher on the well-being scale (p=0.04) and tended to feel less anger (p=0.08) during hyperglycaemia. Self-estimated blood glucose levels were higher during the hyper- than euglycaemic condition (8.6 +/- 2.5 vs 7.2 +/- 1.2 mmol/l; p<0.05) although most individual estimations did not match the actual glucose levels. Counterregulatory hormone levels did not differ (all p>0.25). CONCLUSIONS: Data indicate that T2DM patients are not cognitively impaired by moderate hyperglycaemia (10.5 mmol/l), pointing to the possibility of a glycaemic threshold for cognitive impairments at higher glycaemic levels.

High plasma VEGF relates to low carbohydrate intake in patients with type 2 diabetes.

OBJECTIVE: Vascular endothelial growth factor (VEGF) has been suggested to enhance glucose transport across the blood-brain barrier, thereby increasing brain glucose supply. Increased brain glucose concentration is known to suppress food intake and to decrease body mass via action on hypothalamic regulation centers. Based on the crucial role of VEGF on brain glucose supply, we hypothesized that higher VEGF concentrations are associated with lower food intake and body mass in humans. METHODS: Intending to investigate subjects with high variance of blood glucose, we examined patients with type 2 diabetes mellitus. Our hypothesis was tested in a population-based cohort of 190 subjects with type 2 diabetes. Plasma VEGF levels in conjunction with other parameters known to modulate food intake were measured and subsequently correlated with food intake patterns at a breakfast buffet as well as with body mass. RESULTS: We found that subjects with higher concentrations of plasma VEGF had 17% less carbohydrate intake (P=0.003) and 4.8% lower body mass (P=0.017) than those with lower VEGF concentrations. Intake of protein and fat did not correlate with VEGF concentrations. These associations of plasma VEGF were confirmed in multiple linear regression analyses controlling for several parameters interacting with food intake. CONCLUSION: We conclude that high plasma VEGF concentrations are associated with less carbohydrate intake and lower body mass in type 2 diabetes. The role VEGF plays in facilitating glucose access to the brain represents a new aspect of food intake regulation and energy homeostasis, with relevance for diseases with body mass disturbances.

A pilot phase 2 study of oregovomab murine monoclonal antibody to CA125 as an immunotherapeutic agent for recurrent ovarian cancer.

This prospective, open-label, pilot phase 2 study examined the clinical and immunologic effects of oregovomab (OvaRex) in heavily pretreated patients with recurrent ovarian cancer (OC). Thirteen women were administered intravenous oregovomab (2 mg) at weeks 0, 2, 4, 8, and 12, followed by quarterly doses for up to 2 years or disease progression. Concomitant chemotherapy was not permitted. Eligibility criteria included recurrence after one or more platinum-based chemotherapy regimens, CA125 >35 U/mL, evaluable or measurable disease. Tumor burden was evaluated by physical or radiologic methods pretreatment, weeks 12, 24, and every 24 weeks thereafter. Immune responses, including antibodies and T cells to oregovomab and CA125, were demonstrated in over half the patients. Stabilization of disease and survival >2 years was observed in 3 of 13 patients and coincided with robust immune responses. Shrinkage of marker lesions was not observed; however, four patients showed decreases in CA125 levels. Treatment was well tolerated without serious adverse events or discontinuations due to therapy. This pilot study supports immunologic activity and safety of oregovomab in recurrent OC. Further study of this agent in the consolidation and adjuvant setting is ongoing to establish its clinical utility.